The high incidence of human neonatal morbidity and mortality associated with low birth weight and prematurity indicates need for more intensive study of the mechanisms underlying placental and fetal development. The long-term objective of this research proposal is to improve knowledge in this area by building on our previous in vivo studies in the pregnant baboon which demonstrate that estrogen plays an integrative role in placental-fetal communication by regulating maturation of the placenta and fetal adrenal gland. Study I will test the hypothesis that early in gestation estrogen stimulates vascular endothelial growth/permeability factor and/or angiopoietin-1/-2 formation by villous trophoblasts and thus placental angiogenesis, and concurrently regulates expression of integrins-adhesion molecules by extravillous cytotrophoblasts to restrain their invasion of uterine spiral arteries, and that via these actions estrogen coordinates angiogenesis and placentation to ensure fetal-placental development. The goals of Studies I and II are interwoven to test the hypothesis that estrogen acts on the newly vascularized placenta to regulate expression of sodium-hydrogen exchangers (NHE-1 and -3) and their regulatory factors in the syncytiotrophoblast, directly (NHE-1), and indirectly by regulating the 11beta-hydroxysteroid dehydrogenase enzymes and thus local cortisol levels (NHE-3) to ensure placental-fetal homeostasis. Studies II and III are integrated to test the hypothesis that estrogen acts on the fetal adrenal to promote development of the transitional zone and restrain growth and development of the fetal zone, and that this in utero programming governs adrenal maturation and function in adulthood. Molecular, histological, biochemical, and in vivo physiological parameters of placental trophoblast and fetal adrenal development will be determined in baboons in which estrogen levels are prematurely elevated by estradiol administration or suppressed by a specific aromatase inhibitor. The estrogen-depleted/-repleted pregnant baboon provides a unique primate model to investigate the effects of altered trophoblast function on fetal-neonatal maturation, studies which cannot be performed in pregnant women or with in vitro approaches. Completion of the proposed study will provide new insight into communication between the fetus and placenta and improve our knowledge of the regulation of fetal development and neonatal self-sufficiency.